This invention relates to the use of specific proteins to inhibit pro-inflammatory mediator release from basophils and mast cells in mammals.
Basophils and mast cells are "primary allergic" cells in that they release numerous pro-inflammatory mediators that give rise to inflammatory, e.g., allergic, diseases, which include a wide range of disorders such as allergic rhinitis, urticaria, allergic conjunctivitis, atopic dermatitis, and allergic contact dermatitis. One of the most prevalent allergic diseases is asthma. It is estimated that 5% of the population of industrialized countries suffer from asthma. In the United States, reported cases of asthma have risen from 3% in 1979 to 4% in 1987, with over 10 million people currently affected.
Asthma is defined as an inflammation of the airways associated with bronchial hyper-responsiveness and bronchoconstriction, causing intermittent wheezing and coughing. Asthma is associated with airway inflammation, increased mucous secretion, mucosal edema, smooth muscle contraction, mast cell degranulation, and bronchial hyper-responsiveness. It is currently believed that asthma and other allergic diseases are caused by hypersensitivity reactions induced by primary allergic cells, i.e., basophils and mast cells, which are highly specialized effector cells of the immune system. Both cells store and synthesize large quantities of various mediators of inflammation, and express high affinity IgE receptors. These pro-inflammatory mediators include, e.g., histamine, tryptase (from mast cells), leukotrienes (C.sub.4, D.sub.4, E.sub.4), Platelet Activating Factor (PAF), a variety of cytokines, and other neutral proteases.
Basophils and their mediators are involved, for example, in "cutaneous basophil hypersensitivity," and in the so-called "late phase allergic reaction" in the upper airways and skin; however, the mechanism responsible for protracted histamine release seen during this late phase allergic reaction remains obscure. The late phase appears four to six hours after an allergen-dependent immediate hypersensitivity reaction, and it seems that factors other than allergen or IgE antibody are responsible for basophil and/or mast cell secretion during that time.
In 1979, Thueson et al. reported that the crude supernatant of mononuclear cell cultures contain a factor (Histamine Releasing Factor or HRF) which stimulates basophils and/or mast cells to release histamine. J. Immunol., 122:623 (1979). Dvorak et al. later described that HRF is also chemotactic for basophils. Clin. Immunol. Immunopathol., 32:142 (1984). A major constituent of HRF activity is so-called Monocyte Chemotactic and Activating Factor/Monocyte Chemoattractant Protein-1 (MCAF/MCP-1), which is the most potent protein to release histamine from basophils. See, e.g., Kuna et al., J. Exp. Med., 175:489 (1992) and Alam et al., J. Clin. Invest., 89:723 (1992).
HRFs such as MCAF/MCP-1 are thought to contribute significantly to the protracted histamine release and basophil and/or mast cell degranulation seen in a wide variety of immunologic disorders including inflammatory diseases such as scleroderma and rheumatoid arthritis, and allergic diseases such as chronic urticaria, atopic dermatitis, and asthma, although the specific contribution of MCAF/MCP-1 to histamine release in such disorders has not yet been determined. However, MCAF/MCP-1 has been recently reported to be elevated in the synovial fluid of patients with rheumatoid arthritis. Koch et al., J. Clin. Invest., 90:772 (1992). The mean concentration found was 25.5.+-.8.1 ng/ml which corresponds to 3.times.10.sup.-9 M, at which concentration it is both a chemotactic factor and activates basophils to release histamine.
In addition, other proteins such as RANTES (which stands for "regulated upon" activation, normal T cell expressed and presumably secreted), Connective Tissue Activating Peptide III (CTAP-III), and Interleukin-8 (IL-8) have been shown to induce basophils to release histamine. See, e.g., Kuna et al., J. Immunol., 149:636 (1992); and Bischoff et al., Biochem. Biophys. Res. Commun., 179:628-33 (1991).
Soon after the concept of HRF was reported, mononuclear cell supernatants were also found to contain an inhibitor of HRF-dependent histamine release; the activity was designated Histamine Release Inhibitory Factor (HRIF). Alam et al., J. Clin. Invest., 82:2056 (1988). IL-8 has been shown to fulfill the function attributed to HRIF since preincubation of basophils with IL-8 inhibit HRF and MCAF/MCP-1-induced histamine release. Kuna et al., J. Immunol. 147:1920-1924 (1991). More recently, RANTES was shown by applicants, and then others, to inhibit HRF or MCAF/MCP-1 induced histamine release. Kuna et al., J. Immunol., 149:636 (1992); Alam et al., Am. J. Respir. Cell Mol. Biol., 7:427 (1992).
It has also been shown that basophils are "primed" and augment their secretion of histamine if preincubated with Interleukin-3 (IL-3), IL-5, or Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). See, e.g., Hirai et al., J. Immunol., 141:3958 (1988); Hirai et al., J. Exp. Med., 172:1525 (1990); Dahinden et al., J. Exp. Med., 170:1787 (1989); and Kuna et al., J. Exp. Med., 175:489 (1992).
The treatment of respiratory allergic diseases such as asthma has undergone fundamental changes over the last decade. Emphasis has shifted from making the patient as comfortable as possible by eliminating bronchoconstricting symptoms to treating the underlying condition of the inflammatory response of the airways so as to prevent long-term bronchial destruction. The two primary goals in the management of asthma are to limit bronchial hyper-responsiveness and reduce inflammation of the airways.
First line anti-inflammatory therapy for asthma is the use of inhaled steroids, which are often used concomitantly with inhaled .beta.-agonist-type bronchodilators. Beta-agonists used in this fashion provide prompt relief with few side effects. However, a growing number of studies suggests that one of these .beta.-agonists, fenoterol, may be responsible for an increasing number of deaths of asthmatic patients. Beta-agonists are also contraindicated in patients with coronary disease, as these drugs increase the heart rate. Inhaled cromolyn sodium can be added to such regimens when further therapy is needed. Antihistamines are commonly used to treat allergic rhinitis and urticaria, but often lack complete efficacy and are ineffective against asthma.
Adjunctive therapy includes the use of oral or intravenous theophylline, a bronchodilator used to prevent broncho-constriction, and/or oral .beta.-agonists. These have narrow therapeutic spectrums and side effects are common. Oral corticosteroids are used in refractory patients; however, low doses are not always effective, and high doses have serious adverse effects due to their toxicity. For example, high blood levels of corticosteroids are associated with Cushing's Syndrome, osteoporosis, and cataracts. As a result, none of the currently available treatment regimens are effective in curing asthma, or in substantially avoiding adverse side effects.